Process for producing tricyclic fused heterocyclic derivative

ABSTRACT

A process for easily and industrially advantageously producing both a tricyclic fused heterocyclic derivative having acetylcholinesterase inhibitory activity and an intermediate for the derivative. The process for producing the target compounds comprises the following reaction.

TECHNICAL FIELD

[0001] The present invention relates to a process for producing atricyclic fused heterocyclic derivative having acetylcholinesteraseinhibitory activity which is useful as a medicament and an intermediatethereof.

BACKGROUND TECHNIQUE

[0002] Until now, as a process for synthesizing a tricyclic fusedheterocyclic derivative having acetylcholinesterase inhibitory activityand an intermediate thereof, Friedel-Crafts reaction of a tricyclicfused heterocyclic ring with an acid chloride in the presence ofaluminium chloride in a halogen solvent has been reported (JP 7-206854A).

OBJECTS OF THE INVENTION

[0003] Since in the aforementioned previous process, 1,2-dichloroethaneand methylene chloride which are an environmental pollutant and areremarkably restricted in their use are used as a reaction solvent, andmany steps are involved, it is desired to develop a process forproducing a tricyclic fused heterocyclic derivative and an intermediatethereof, which is inexpensive and simple.

SUMMARY OF THE INVENTION

[0004] The present inventors studied various processes for producing atricyclic fused heterocyclic derivative and, as a result, found for thefirst time that when a tricyclic fused heterocyclic ring and apiperidinecarboxylic acid derivative are subjected todehydration-condensation in the presence of a polyphosphoric acid, thepiperidinecarboxylic acid derivative is bound to a particular desiredposition of the tricyclic fused heterocyclic ring, thereby obtaining thedesired derivative at a better yield and at the low cost and simply, andthat this process is a satisfactory industrial process. Based on thesefindings, the present inventors intensively studied and completed thepresent invention.

[0005] That is, the present invention relates to:

[0006] (1) A process for producing a compound represented by theformula:

[0007] wherein the symbols are as defined hereinafter, or a saltthereof, which comprises:

[0008] reacting a compound represented by the formula:

[0009] wherein one of the ring A and the ring B is an optionallysubstituted heterocyclic ring, and the other is an optionallysubstituted 5- to 8-membered ring which may contain hetero atom(s), or asalt thereof, with a compound represented by the formula:

[0010] wherein R is a hydrogen atom, an optionally substituted alkylgroup or an optionally substituted acyl group, and n is an integer of 1to 6, or a salt thereof, in the presence of a phosphorus compound;

[0011] (2) The process according to the above (1), wherein thephosphorus compound is polyphosphoric acid;

[0012] (3) The process according to the above (1), wherein the formula:

[0013] wherein each of the ring A″ and the ring B″ ring is an optionallysubstituted nitrogen-containing heterocyclic ring;

[0014] (4) The process according to the above (1), wherein R is anoptionally substituted acyl group;

[0015] (5) The process according to the above (1), wherein R is anacetyl group;

[0016] (6) A process for producing8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound;

[0017] (7) A process for producing a compound represented by theformula:

[0018] wherein the symbols are as defined hereinafter, or a saltthereof, which comprises:

[0019] reacting a compound represented by the formula:

[0020] wherein one of the ring A and the ring B is an optionallysubstituted heterocyclic ring, and the other is an optionallysubstituted 5- to 8-memberd ring which may contain hetero atom(s), or asalt thereof, with a compound represented by the formula:

[0021] wherein R′ is an optionally substituted acyl group, and n is aninteger of 1 to 6, in the presence of a phosphorus compound, and

[0022] deacylating the resulting compound represented by the formula:

[0023] wherein the symbols are as defined above, or a salt thereof;

[0024] (8) The process according to the above (7), wherein deacylationis conducted with about 1 to about 6 N hydrochloric acid;

[0025] (9) A process for producing8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound, and deacetylating the resulting8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one;

[0026] (10) A process for producing a compound represented by theformula:

[0027] wherein the symbols are as defined hereinafter, or a saltthereof, which comprises:

[0028] reacting a compound represented by the formula:

[0029] wherein one of the ring A ring and the ring B is an optionallysubstituted heterocyclic ring, and the other is an optionallysubstituted 5- to 8-membered ring which may contain hetero atom(s), or asalt thereof, with a compound represented by the formula:

[0030] wherein R′ is an optionally substituted acyl group, and n is aninteger of 1 to 6, or a salt thereof, in the presence of a phosphoruscompound,

[0031] deacylating the resulting compound represented by the formula:

[0032] wherein the symbols are as defined, or a salt thereof, and

[0033] reacting the resulting compound represented by the formula:

[0034] wherein the symbols are as defined above, or a salt thereof, witha compound represented by the formula:

[0035] wherein the ring C is an optionally substituted benzene ring, andW is a leaving group, or a salt thereof;

[0036] (11) The process according to the above (10), wherein the ring Cis a benzene ring substituted with a halogen;

[0037] (12) A process for producing8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound, deacetylating the resulting8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,and reacting the resulting8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-onewith 3-fluorobenzyl chloride; and the like.

DETAILED EXPLANATION OF THE INVENTION

[0038] As the “heterocyclic ring” in the “optionally substitutedheterocyclic ring” represented by the ring A or the ring B in the aboveformulas, for example, a 5- to 9-membered ring containing 1 to 3 heteroatom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atomis used. Specifically, for example, pyridine, pyrazine, pyrimidine,imidazole, furan, thiophene, pyrrolidine, piperidine,hexamethyleneimine, tetrahydrofuran, piperazine, morpholine,thiomorpholine, etc., are used. In particular, a 5- to 9-memberednon-aromatic heterocyclic containing one hetero atom or the same ordifferent two hetero atoms (e.g. pyrrolidine, piperidine,hexamethyleneimine, tetrahydrofuran, piperazine, morpholine,thiomorpholine, etc.) is preferable. In particular, for example, anon-aromatic heterocyclic ring containing one hetero atom selected froma nitrogen atom, an oxygen atom and a sulfur atom, and a non-aromaticheterocyclic ring containing one nitrogen atom and one hetero atomselected from a nitrogen atom, an oxygen atom and a sulfur atom arefrequently used.

[0039] As the “5- to 8-membered ring which may contain hetero atom(s)”represented by the ring A or the ring B, a 5- to 8-membered heterocyclicor carbocyclic ring is used, and the ring may be substituted. The 5- to8-membered carbocyclic ring may be a benzene ring, or a saturated orunsaturated ring and, for example, benzene, cyclopentane, cyclopentene,cyclohexane, cyclohexene, cyclohexadiene, cycloheptane, cycloheptene,cycloheptadiene, etc., are used. In addition, when the ring A or thering B has hetero atom(s) in the ring, that is, the ring A or the ring Bis a heterocyclic ring, as the hetero atom(s), for example, 1 to 3atom(s) selected from a nitrogen atom, an oxygen atom and a sulfur atomis (are) used, and the ring A or the ring B may be either aromatic ornon-aromatic. As the aromatic heterocyclic ring, pyridine, furan,thiophene, etc., are used. As the non-aromatic heterocyclic ring, anon-aromatic heterocyclic ring exemplified with respect to the ring A orthe ring B is preferable.

[0040] That is, examples of the compound (I) include1H,3H-naphtho[1,8-cd][1,2]oxazine, naphtho[1,8-de]-1,3-oxazine,naphtho[1,8-de]-1,2-oxazine, 1,2,2a,3,4,5-hexahydrobenzo[cd]indole,2,3,3a,4,5,6-hexahydro-1H-benzo[de]quinoline,4H-pyrrolo[3,2,1-ij]quinoline,1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline,5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, 1H,5H-benzo[ij]quinolizine,azepino[3,2,1-hi]indole, 1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]indole,1H-pyrido[3,2,1-jk][1]benzazepine,5,6,7,8-tetrahydro-1H-pyrido[3,2,1-jk][1]benzazepine,1,2,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine,2,3-dihydro-1H-benzo[de]isoquinoline,1,2,3,4,4a,5,6,7-octahydronaphtho[1,8-bc]azepine,2,3,5,6,7,8-hexahydro-1H-pyrido[3,2,1-jk][1]benzazepine, and the like.

[0041] As the compound (1), for example, a compound represented by theformula:

[0042] wherein R⁶ is a hydrogen atom, an optionally substitutedhydrocarbon group or an optionally substituted acyl group, and the othersymbols are as defined above, or a salt thereof is preferable.

[0043] As the compound (I), a compound represented by the formula:

[0044] wherein the ring A′ is an optionally substituted 5- or 6-memberednitrogen-containing heterocyclic ring, and the ring B′ is an optionallysubstituted 5- to 7-membered nitrogen-containing heterocyclic ring, or asalt thereof, that is, a compound represented by the formula:

[0045] wherein the symbols are as defined above, or a salt thereof ismore preferable.

[0046] As the compound (I), a compound represented by the formula:

[0047] wherein each of the ring A″ and the ring B″ is an optionallysubstituted nitrogen-containing heterocyclic ring, or a salt thereof ismost preferable.

[0048] The ring A and the ring B may be substituted, and the substituentmay be present at any arbitrary carbon atom of the ring A and the ringB. As the substituent(s), for example, 1 to 5 substituent(s) selectedfrom a halogen atom (e.g. fluoro, chloro, bromo, iodo, etc.), a nitrogroup, a cyano group, an oxo group, a hydroxy group, a C₁₋₄alkoxy group(e.g. methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy, etc.), aC₁₋₄alkylthio group (e.g. methylthio, ethylthio, propylthio, etc.), anamino group, a mono-or di-C₁₋₄alkylamino group (e.g. methylamino,ethylamino, propylamino, dimethylamino, diethylamino, etc.), a 5- to7-membered cyclic amino group which may have 1 to 3 hetero atom(s), forexample, selected from a nitrogen atom, an oxygen atom and a sulfur atomin addition to carbon atoms and one nitrogen atom (e.g., pyrrolidino,piperidino, morpholino, thiomorpholino, etc.), a C₁₋₄alkyl-carbonylaminogroup (e.g. acetylamino, propionylamino, butyrylamino, etc.), aC₁₋₄alkylsufonylamino group (e.g. methylsulfonylamino,ethylsulfonylamino, etc.), a C₁₋₄alkoxy-carbonyl group (e.g.methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), a carboxylgroup, a C₁₋₆alkyl-carbonyl group (e.g. methylcarbonyl, ethylcarbonyl,propylcarbonyl, etc.), a carbamoyl group, a mono- ordi-C₁₋₄-alkyl-carbamoyl group (e.g. methylcarbamoyl, ethylcarbamoyl,etc.), a C₁₋₆alkylsulfonyl group (e.g. methylsulfonyl, ethylsulfonyl,propylsulfonyl etc.), etc., are used.

[0049] Among them, an oxo group, and a C₁₋₆alkyl group such as methylare preferable and, inter alia, an oxo group is preferable.

[0050] When the ring A and the ring B have a nitrogen atom in the ring,those rings may have a substituent on the nitrogen atom. That is, thering A and the ring B may have

>N—R⁶

[0051] wherein R⁶ is a hydrogen atom, an optionally substitutedhydrocarbon group or an optionally substituted acyl group, in the ring.

[0052] As the “optionally substituted hydrocarbon group” represented byR⁶, for example, a C₁₋₆alkyl group (e.g. methyl, ethyl, n-propyl,isopropyl, etc.) and a C₇₋₁₀aralkyl group (e.g. phenylmethyl,phenylethyl, etc.), etc., which may be substituted with 1 to 3substituent(s) selected from a halogen atom (e.g. fluoro, chloro, bromo,iodo, etc.), a nitro group, a C₁₋₄alkoxy group (e.g. methoxy, ethoxy,etc.), a hydroxy group, etc., are preferable. In particular, anunsubstituted benzyl group is frequently used.

[0053] As the “optionally substituted acyl group” represented by R⁶, forexample, formyl, C₁₋₆alkyl-carbonyl (e.g. acetyl, propionyl, etc.),benzoyl, C₁₋₆alkylsulfonyl (e.g. methanesulfonyl, ethanesulfonyl, etc.),benzenesulfonyl, C₁₋₆alkoxy-carbonyl (e.g. methoxycarbonyl,ethoxycarbonyl, t-butoxycarbonyl, etc.), benzyloxycarbonyl, etc., whichmay be substituted with 1 to 3 substituent(s) selected from a halogenatom (e.g. fluoro, chloro, bromo, iodo, etc.), a nitro group, aC₁₋₆alkoxy group (e.g. methoxy, ethoxy, etc.), a hydroxy group, an aminogroup, a mono- or di-C₁₋₆alkylamino group (e.g. methylamino, ethylamino,dimethylamino, diethylamino, etc.), etc., are preferable.

[0054] In the aforementioned formulas, examples of a substituent in thering A′, the ring B′, the ring A″ and the ring B″ include the samesubstituents as those in the ring A and the ring B.

[0055] As the substituent of the ring A′ and the ring B′, an oxo groupis preferable, and the ring A″ and the ring B″ are preferablyunsubstituted.

[0056] In the aforementioned formulas, examples of the “optionallysubstituted alkyl group” represented by R include a C₁₋₆alkyl group(e.g. methyl, ethyl, n-propyl, isopropyl, etc.) optionally substitutedwith 1 to 3 substituent(s) selected from (1) a halogen atom (e.g.fluoro, chloro, bromo, iodo, etc.), (2) nitro group, (3) a C₁₋₆alkoxygroup (e.g. methoxy ethoxy, etc.), (4) a hydroxy group, (5) a phenylgroup optionally substituted with 1 to 3 substituent(s) selected fromC₁₋₆alkyl (e.g. methyl, ethyl, etc.), a halogen atom (e.g. fluoro,chloro, bromo, iodo, etc.), nitro, cyano, amino, mono- ordi-C₁₋₆alkylamino (e.g. methylamino, ethylamino, dimethylamino,diethylamino, etc.), hydroxy, C₁₋₆alkoxy (e.g. methoxy, ethoxy, etc.),phenyl-C₁₋₆alkoxy (e.g. benzyloxy, etc.), C₁₋₄alkylenedioxy (e.g.methylenedioxy, etc.), etc.

[0057] Examples of the “optionally substituted acyl group” representedby R and R′ include the same “optionally substituted acyl group” as thatrepresented by R⁶.

[0058] As R and R′, an optionally substituted acyl group is preferable,and a C₁₋₆alkyl-carbonyl group (e.g. acetyl group) is more preferable.

[0059] In the aforementioned formulas, while n is an integer of 1 to 6,2 or 3 are preferable, and 2 is more preferable.

[0060] In the aforementioned formulas, examples of the “optionallysubstituted benzene ring” represented by the ring C include a benzenering optionally substituted with 1 to 3 substituent(s) selected fromC₁₋₆alkyl (e.g. methyl, ethyl, etc.), halogen atom (e.g. fluoro, chloro,bromo, iodo, etc.), nitro, cyano, amino, mono-or di-C₁₋₆alkylamino (e.g.methylamino, ethylamino, dimethylamino, diethylamino, etc.), hydroxy,C₁₋₆alkoxy (e.g. methoxy, ethoxy, etc.), phenyl-C₁₋₄alkoxy (e.g.benzyloxy, etc.) and C₁₋₄alkylenedioxy (e.g. methylenedioxy, etc.).

[0061] As the ring C, a benzene ring substituted with a halogen atomsuch as fluoro, etc., amino, etc., is preferable, and a benzene ringsubstituted with a halogen atom is more preferable.

[0062] Examples of the “leaving group” represented by W in the aboveformulas include a halogen atom (e.g. chloro, bromo, iodo, etc.),optionally halogenated C₁₋₆alkylsulfonyloxy (e.g. methanesulfonyloxy,ethanesulfonyloxy, trifluoromethanesulfonyloxy, etc.), optionallysubstituted C₆₋₁₀arylsulfonyloxy, etc. Examples of the substituent ofthe “optionally substituted C₆₋₁₀arylsulfonyloxy” include 1 to 3substituent(s) selected from a halogen atom, optionally halogenatedC₁₋₆alkyl and optionally halogenated C₁₋₆ halogenated alkoxy. Examplesof the “optionally substituted C₆₋₁₀arylsulfonyloxy” includebenzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy,2-naphthalenesulfonyloxy, etc.

[0063] As W, a halogen atom such as chloro is preferable.

[0064] As a salt of the compounds represented by the formulas (I), (II),(II′), (III), (III′), (IV) and (V), for example, salts with inorganicacids (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid,sulfuric acid, nitric acid, etc.), or salts with organic acids (e.g.acetic acid, trifluoroacetic acid, formic acid, propionic acid, fumaricacid, maleic acid, succinic acid, tartaric acid, citric acid, malicacid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, etc.) are used. Further, when eachcompound has an acidic group such as —COOH, the compound may form a saltwith inorganic bases (e.g. alkali metal and alkaline earth metal such assodium, potassium, calcium and magnesium, etc., and ammonia) or organicbases (e.g. triethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,N,N-dibenzylethylenediamine, etc.).

[0065] A process for producing the compound (III), (IV) or (VI) which isuseful as a tricyclic fused heterocyclic derivative havingacetylcholinesterase inhibitory activity and an intermediate thereofwill be described below.

[0066] In the process of the present invention, a compound (I) and acompound (II) are subjected to dehydration-condensation in the presenceof a phosphorus compound to obtain a compound (III).

[0067] The amount of the compound (II) to be used is about 1 to 10moles, preferable about 1 to 2 moles relative to 1 mole of the compound(I).

[0068] Examples of the phosphorus compound used in the present inventioninclude 1 or 2 or more selected from polyphosphoric acid, polyphosphoricacid ester, phosphorus pentaoxide, phosphorus pentaoxide-phosphoricacid, phosphorus pentaoxide-methanesulfonic acid, phosphorusoxychloride-zinc (II) chloride, etc. Among them, polyphosphoric acid ispreferable.

[0069] The amount of the phosphorus compound to be used is about 1 to100 moles, preferably about 1 to 20 moles relative to 1 mole of thecompound (II).

[0070] The reaction temperature is usually about 0 to 160° C.,preferable about 20 to 120° C. The reaction time is usually about 0.1 to30 hours, preferably about 1 to 10 hours.

[0071] In this reaction, it is preferable that the phosphorus compoundis used as it is as a solvent. The reaction may be carried out in thepresence of a solvent which is inert to the reaction. As the “inertsolvent”, aromatic hydrocarbons (e.g. benzene, toluene, xylene,chlorobenzene, etc.), ethers (e.g. diglyme, diethyl ether, diisopropylether, t-butyl methyl ether, diphenyl ether, dioxane,1,2-dimethoxyethane, etc.), aliphatic hydrocarbons (e.g. hexane,pentane, cyclohexane, etc.), amides (e.g. N,N-dimethylformamide,N,N-dimethylacetamide, 1-methyl-2-pyrrolidone,hexamethylphosphorictriamide, etc.), nitrites (e.g. acetonitrile,propionitrile, etc.), and a mixture of 2 or more thereof may be used.Among them, toluene, tetrahydrofuran, N,N-dimethylformamide, etc., arepreferable.

[0072] When the compound (I) and the compound (II) are commerciallyavailable, they may be used as they are, or those compounds may beprepared by a method known per se (JP-A 7-206854) or a similar method.

[0073] Next, a compound wherein R is an optionally substituted acylgroup in the formula (III), that is, a compound (III′) may be furtherdeacylated to obtain a compound (IV).

[0074] In this reaction, a deacylating agent such as hydrochloric acid,hydrobromic acid, sulfuric acid and the like is usually used. Amongthem, hydrochloric acid is preferable, and the concentration ofhydrochloric acid is preferably about 1 to 12 N, more preferably about 1to 6 N.

[0075] The amount of the deacylating agent to be used is about 1 to 50moles, preferably about 2 to 5 moles relative to 1 mole of the compound(IV).

[0076] The reaction temperature is usually about 20 to 120° C.,preferably about 60 to 100° C. The reaction time is usually about 0.1 to30 hours, preferably about 1 to 15 hours.

[0077] In this reaction, 1 to 12 N hydrochloric acid is used as it is asa solvent in some cases, but the reaction may also be carried out in thepresence of a solvent which is inert to the reaction. As the “inertsolvent”, aromatic hydrocarbons (e.g. benzene, toluene, xylene,chlorobenzene, etc.), ethers (e.g. diglyme, diethyl ether, diisopropylether, t-butyl methyl ether, diphenyl ether, dioxane,1,2-dimethoxyethane, etc.), aliphatic hydrocarbons (e.g. hexane,pentane, cyclohexane, etc.), alcohols (e.g. methanol, ethanol, isopropylalcohol, 2-butanol, t-butanol, 2-methyl-2-butanol, etc.), and a mixtureof 2 or more thereof may be used. Among them, toluene, tetrahydrofuranand ethanol are preferable.

[0078] Then, the thus obtained compound (IV) or a compound wherein R isa hydrogen atom in the formula (III) and a. compound (V) are reacted inthe presence or the absence of a base to obtain a compound (VI).

[0079] The amount of the compound (V) to be used is about 1 to 10 moles,preferably about 1 to 3 moles relative to 1 mole of the compound (IV).

[0080] Examples of the “base” include hydrides of an alkali metal or analkaline earth metal (e.g. lithium hydride, sodium hydride, potassiumhydride, calcium hydride, etc.), amides of an alkali metal or analkaline earth metal (e.g. lithium amide, sodium amide, lithiumdiisopropylamide, lithium dicyclohexylamide, lithiumhexamethyldisilazide, sodium hexamethyldisilazide, potassiumhexamethyldisilazide, etc.), lower alkoxides of an alkali metal or analkaline earth metal (e.g. sodium methoxide, sodium ethoxide, potassiumtert-butoxide, etc.), carbonates of an alkali metal or an alkaline earthmetal (e.g. sodium bicarbonate, sodium carbonate, potassium carbonate,etc.), organic bases (e.g. organic bases such as amines such astriethylamine, diisopropylethylamine, N-methylmorpholine,dimethylaminopyridine, DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), DBN(1,5-diazadicyclo[4.3.0]non-5-ene), etc.; basic heterocyclic compoundssuch as pyridine, imidazole, and 2,6-lutidine, etc.), etc. Among them,carbonates of an alkali metal or an alkaline earth metal are preferable.The amount of the “base” to be used is about 1 to 10 moles, preferablyabout 1 to 3 moles relative to 1 mole of the compound (V).

[0081] The reaction temperature is usually about −10 to 150° C.,preferably about 0 to 80° C. The reaction time is usually about 0.1 to30 hours, preferably about 1 to 15 hours.

[0082] This reaction is carried out in the presence of a solvent whichis inert to the reaction. As the “inert solvent”, for example, aromatichydrocarbons (e.g. benzene, toluene, xylene, chlorobenzene, etc.),ethers (e.g. diethyl ether, diisopropyl ether, t-butyl methyl ether,diphenyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.),aliphatic hydrocarbons (e.g. hexane, pentane, cyclohexane, etc.), amides(e.g. N,N-dimethylformamide, N,N-dimethylacetamide,1-methyl-2-pyrrolidone, hexamethylphosphorictriamide, etc.), sulfoxides(e.g. dimethyl sulfoxide, etc.), primary alcohols (e.g. methanol,ethanol, etc.), nitrites (e.g. acetonitrile, propionitril, etc.), waterand a mixture of 2 or more thereof are used. Among them,N,N-dimethylformamide, ethanol, acetonitrile, etc., are preferable.

[0083] This reaction is carried out in the presence of an inorganic salt(e.g. halogenated alkali metal salt such as sodium iodide, sodiumbromide, potassium iodide, potassium bromide, etc.) as necessary.

[0084] The thus obtained compound (III), (IV) or (VI) can be isolatedand purified from a reaction mixture by a separating means known per se(e.g. concentration, concentration under reduced pressure, solventextraction, precipitation, recrystallization, transferring dissolution,chromatography, etc.).

[0085] The desired end compounds [compound (III) (except that R is ahydrogen atom) and compound (VI)] have acetylcholinesterase inhibitoryactivity. Therefore, these compounds are useful as an agent forpreventing or treating senile dementia. Further, they can be used as abladder excretion modifier. For example, they can be used as an agentfor preventing or treating urination disorder caused by the following 1)to 6), in particular, urination difficulty: 1) prostatomegary, 2)bladder cervical obstruction, 3) neurogenic bladder, 4) diabetes, 5)operation and 6) bladder muscle tension reduction. Further, they arealso useful as an agent for preventing or treating urination disordersuch as pollakiuria, urinal incontinence and the like.

[0086] The following Examples illustrate the present invention in moredetail but do not limit the present invention.

[0087] Abbreviations used in the present text have the followingmeanings.

[0088] s: singlet

[0089] d: doublet

[0090] t: triplet

[0091] m: multiplet

[0092] J: coupling constant

[0093] Hz: Hertz

[0094] CDCl₃: heavy chloroform

[0095] DMSO-d₆: heavy dimethyl sulfoxide

[0096]¹H-MMR: proton nuclear magnetic resonance

[0097]¹H-NMR spectrum is measured with Brukka DPX 300 (300MHz) typespectrometer using tetramethylsilane as an internal standard, and thetotal δ value is shown in ppm.

EXAMPLE 1

[0098] Synthesis of8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

[0099] A mixture of 2.5 kg of 1-acetyl-4-piperidinepropionic acid, 2.17kg (1 equivalent) of1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one and 26.0 kg ofpolyphosphoric acid was stirred at about 105° C. for 8 hours undernitrogen and 13 L of cold water at about 5° C. was slowly added dropwisethereto while maintaining about 70° C. Further, 25 L of a mixture oftoluene-acetonitrile (1:1) was added at about 55° C. and pH was adjustedto about 8.5 by adding 25% aqueous ammonia solution (about 50 L) whilemaintaining about 55° C. The layers were separated, 10 L of a mixture oftoluene-acetonitrile (1:1) was added to the aqueous layer, and thelayers were separated. The organic layers were combined and concentratedto a volume of the solution of about 10 L. To the residue was added 9 Lof isopropyl ether at about 20° C. to precipitate crystals. The mixturewas stirred at about 20° C. for about 1.5 hours and then at about 5° C.for about 1.5 hours. Precipitated crystals were separated, washed withabout 6 L of a mixture of isopropyl ether-ethyl acetate (1:1) cooled toabout 5° C., and 10 L of isopropyl ether cooled to about 5° C., anddried to obtain 3.78 kg (yield 85%) of the desired compound as crystals.

[0100] Elementary Analysis

[0101] Calcd: C: 71.16, H: 7.39, N: 7.90, 0: 13.54

[0102] Found: C: 71.20, H: 7.36, N: 7.80

[0103]¹H-NMR(CDCl₃): 1.13-1.19 (2H, m), 1.64-1.79 (5H, m), 2.09 (3H, s),2.53 (1H, t), 2.72 (2H, t, J=9.7 Hz), 2.93-3.05 (5H, m), 3.23 (2H, t,J=8.4 Hz), 3.80 (1H, d), 4.14 (2H, t, J=8.4 Hz), 5.61 (1H, d), 7.67 (1H,s), 7.72 (1H, s)

EXAMPLE 2

[0104] Synthesis of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

[0105] A mixture of 3.95 kg of8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-oneand 19.8 L of 2 N HCl was stirred at about 85° C. for about 10 hours.After cooled to about 35° C., 12 L of toluene was added to the reactionmixture, the layers were separated, and pH was adjusted to about 13 byadding 30% NaOH (about 10 L) to the aqueous layer while maintainingabout 30° C. Further, 20 L of a mixture of toluene-acetonitrile (1:1)was added thereto, and the layers were separated. To the aqueous layerwas added 12 L of a mixture of toluene-acetonitrile (1:1), and thelayers were separated. The organic layers were combined, 12 L of 30%brine was added thereto, and the layers were separated. To the organiclayer were added 346 g of active carbon and 346 g of silica gel,followed by stirring for about 15 minutes. The insolubles were filteredoff, and washed with 6 L of a mixture of toluene-acetonitrile (1:1). Thefiltrate was concentrated to a volume of the solution of about 7 L. Tothe residue was added 3 L of toluene, and the mixture was stirred atabout 40° C. Under nitrogen, 666 g of acetic acid was added at about 30°C. over about 15 minutes. The mixture was stirred at about 25° C. for1.5 hours and then at about 5° C. for 1 hour. Precipitated crystals wereseparated, and washed with 28 L of a mixture of toluene-acetonitrile(1:1) cooled to about 5° C. The wet crystals were suspended in 65 L of amixture of toluene-acetonitrile (1:1), 30% NaOH was added (about 10 L)thereto, pH was adjusted to 13.5, and the layers were separated. To theaqueous layer was added 8 L of a mixture of toluene-acetonitrile (1:1),and the layers were separated. The organic layers were combined, andwashed with 12 L of 30% brine. The organic layer was washed again with12 L of 30% brine. To the organic layer were added 346 g of activecarbon and 346 g of silica gel, the mixture was stirred for about 15minutes. The insolubles were filtered off, and washed with 6 L of amixture of toluene-acetonitrile (1:1). The same procedures were repeatedtwice. The organic layer was concentrated, and 5 L of water was added tothe residue, followed by re-concentration. The same procedures wererepeated twice. Under nitrogen, 5 L of water was added to the residue,and 5 L of 30% brine was added at about 20° C. over about 15 minutes.Seed crystals were added, and the mixture was stirred at about 20° C.for 1.5 hours and then at about 5° C. for 1 hour. The desired compoundwas separated under nitrogen, washed with 4 L of 30% brine cooled toabout 5° C., and dried to give 1.78 kg (yield 51%) of the desiredcompound as crystals.

[0106] Elementary Analysis

[0107] Calcd: C: 73.05, H: 7.74, N: 8.97, O: 10.24

[0108] Found: C: 72.90, H: 7.65, N: 9.06

[0109]¹H-NMR(CDCl₃): 1.12-1.22 (2H, m), 1.40-1.50 (1H, m), 1.64-1.74(4H, m), 2.59 (2H, td, J=12, 2.4 Hz), 2.72 (2H, t, J=7.5 Hz), 2.93 (2H,t, J=7.5 Hz), 3.00-3.10 (4H, m), 3.23 (2H, t, J=8.4 Hz), 4.13 (2H, t,J=8.4 Hz), 7.67 (1H, s), 7.72 (1H, s)

EXAMPLE 3

[0110] Synthesis of8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

[0111] A mixture of 600 g of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,6 L of acetonitrile, 0.3 L of water, 345 g (1.3 equivalent) of potassiumcarbonate and 278 g (1 equivalent) of 3-fluorobenzyl chloride wasstirred at about 55° C. and 12 L of water was added dropwise theretoover about 20 minutes while maintaining about 45° C. The mixture wasstirred at about 55° C. for 1.5 hours, and at about 20° C. for 3 hours.Precipitated crystals were separated, and washed with 15 L of water. Thewet crystals were suspended in 8.0 L of 10% hydrous methanol-denaturedethanol. The material was dissolved at about 70° C., and passed througha dust-removing filter. The filtrate was stirred at about 20° C. for 1.5hours, 6.9 L of water was added thereto, and the mixture was stirred atabout 20° C. for 3 hours. Crystals were separated, washed with 1.8 L of50% hydrous methanol-denatured ethanol twice and dried to obtain 0.71 kg(yield 88%) of the desired compound as crystals.

[0112] m.p.: 114° C.

[0113] Elementary Analysis

[0114] Calcd: C: 74.26, H: 6.95, N: 6.66, F: 4.52, O: 7.61

[0115] Found: C: 74.27, H: 6.97, N: 6.53, F: 4.52

[0116]¹H-NMR(DMSO-d₆): 1.16 (2H, qd, J=11.9, 3.5 Hz), 1.21-1.30 (1H, m),1.53 (2H, m), 1.64-1.67 (2H, d, J=11.9 Hz), 1.89 (2H, t, J=11.9 Hz),2.59 (2H, t, J=7.8 Hz), 2.77 (2H, d, J=11.9 Hz), 2.94 (2H, t, J=7.6 Hz),2.97 (2H, J=7.8 Hz), 3.17 (2H, t, 8.5 Hz), 3.44 (2H, s), 3.98 (2H, t,J=8.5 Hz), 7.05 (1H, m), 7.10 (1H, d), 7.12 (1H, d, J=7.9 Hz), 7.35 (1H,td, J=7.9, 6.1Hz), 7.72 (1H, m), 7.73 (1H, m)

[0117] IR(KBr, vcm⁻¹): 2020, 1660, 1597, 1491, 1387, 1336, 1128, 802

[0118] UVmax(CH₃CN): 310 nm

EXAMPLE 4

[0119] Synthesis of8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

[0120] A mixture of 1-acetyl-4-piperidinepropionic acid (1.99 g, 9.99mmol), 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one (1.73 g,9.99 mmol) and polyphosphoric acid (24 g) was stirred at about 105° C.for 7 hours under nitrogen. Cold water (16 mL) at about 5° C. was slowlyadded dropwise thereto at −40 to 70° C. and 25% aqueous ammonia wasadded dropwise thereto at 40 to 50° C. to adjust pH to 8.5. A mixture oftoluene-acetonitrile (1:1) (20 mL) was added. The layers were separated,a mixture of toluene-acetonitrile (1:1) (10 mL) was added to the aqueouslayer, and the layers were separated. The organic layers were combined,and concentrated to a volume of the solution of ⅕. Diisoporpyl ether (7mL) was added to the residue to precipitate crystals. The mixture wasstirred at about 25° C. for about 1 hour and then at 0 to 5° C. forabout 1 hour. Precipitated crystals were separated, washed withdiisopropyl ether (3 mL) and dried to obtain 3.47 g (yield 98.6%) of thedesired compound as crystals.

EXAMPLE 5

[0121] Synthesis of8-[3-(4-piperidinyl)-l-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

[0122]8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one(10 g, 28.2 mmol) and 2 N hydrochloric acid (50 mL) were stirred atabout 90° C. for 8 hours. After cooled to about 25° C., toluene (30 mL)was added to the reaction mixture, the layers were separated, and 30%aqueous sodium hydroxide solution (16 mL) was added to the aqueous layerto adjust pH to 13.8. A mixture of toluene-acetonitrile (1:1) (50 mL)was added thereto, and the layers were separated. A mixture oftoluene-acetonitrile (1:1) (50 mL) was added to aqueous layer, and thelayers were separated. The organic layers were combined, 30% brine (30mL) was added, and the layers were separated. The organic layer wasconcentrated under reduced pressure to obtain 8.55 g (yield 92.5%) ofthe desired compound as a solid.

EXAMPLE 6

[0123] Synthesis of8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one

[0124] A mixture of8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one(4 g, 12.8 mmol), acetonitrile (26 mL), water (1.4 mL), potassiumcarbonate (2.3 g, 16.6 mmol) and 3-fluorobenzyl chloride (1.55 mL, 12.8mmol) was stirred at about 50 to 55° C. After cooling, water (84 mL) wasadded dropwise thereto. The mixture was stirred at room temperature forabout 1 hour. Precipitated crystals were separated, washed with water(80 mL) and dried to obtain 5.09 g (yield 95%) of the desired compoundas crystals.

[0125] Industrial Applicability

[0126] According to the process of the present invention, a tricyclicfused heterocyclic derivative having acetylcholinesterase inhibitoryactivity which is useful as a medicament, and an intermediate thereofcan be prepared at a better yield, effectively and at an industriallarge scale by an inexpensive and simple process.

1. A process for producing a compound represented by the formula:

wherein the symbols are as defined hereinafter, or a salt thereof, whichcomprises: reacting a compound represented by the formula:

wherein one of the ring A and the ring B is an optionally substitutedheterocyclic ring, and the other is an optionally substituted 5- to8-membered ring which may contain hetero atom(s), or a salt thereof,with a compound represented by the formula:

wherein R is a hydrogen atom, an optionally substituted alkyl group oran optionally substituted acyl group, and n is an integer of 1 to 6, ora salt thereof, in the presence of a phosphorus compound.
 2. The processaccording to claim 1, wherein the phosphorus compound is apolyphosphoric acid.
 3. The process according to claim 1, wherein theformula:

wherein each of the ring A″ and the ring B″ ring is an optionallysubstituted nitrogen-containing heterocyclic ring.
 4. The processaccording to claim 1, wherein R is an optionally substituted acyl group.5. The process according to claim 1, wherein R is an acetyl group.
 6. Aprocess for producing8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound.
 7. A process for producing a compound represented by theformula:

wherein the symbols are as defined hereinafter, or a salt thereof, whichcomprises: reacting a compound represented by the formula:

wherein one of the ring A and the ring B is an optionally substitutedheterocyclic ring, and the other is an optionally substituted 5- to8-memberd ring which may contain hetero atom(s), or a salt thereof, witha compound represented by the formula:

wherein R′ is an optionally substituted acyl group, and n is an integerof 1 to 6, in the presence of a phosphorus compound, and deacylating theresulting compound represented by the formula:

wherein the symbols are as defined above, or a salt thereof.
 8. Theprocess according to claim 7, wherein deacylation is conducted withabout 1 to about 6 N hydrochloric acid.
 9. A process for producing8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound, and deacetylating the resulting8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one.10. A process for producing a compound represented by the formula:

wherein the symbols are as defined hereinafter, or a salt thereof, whichcomprises: reacting a compound represented by the formula:

wherein one of the ring A ring and the ring B is an optionallysubstituted heterocyclic ring, and the other is an optionallysubstituted 5- to 8-membered ring which may contain hetero atom(s), or asalt thereof, with a compound represented by the formula:

wherein R′ is an optionally substituted acyl group, and n is an integerof 1 to 6, or a salt thereof, in the presence of a phosphorus compound,deacylating the resulting compound represented by the formula:

wherein the symbols are as defined, or a salt thereof, and reacting theresulting compound represented by the formula:

wherein the symbols are as defined above, or a salt thereof, with acompound represented by the formula:

wherein the ring C is an optionally substituted benzene ring, and W is aleaving group, or a salt thereof.
 11. The process according to claim 10,wherein the ring C is a benzene ring substituted with a halogen.
 12. Aprocess for producing8-[3-[1-[(3-fluorophenyl)methyl]-4-piperidinyl]-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,which comprises reacting1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one with1-acetyl-4-piperidinepropionic acid in the presence of a phosphoruscompound, deacetylating the resulting8-[3-(1-acetyl-4-piperidinyl)-1-oxopropyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,and reacting the resulting8-[3-(4-piperidinyl)-1-oxopropyl]-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline-4-onewith 3-fluorobenzyl chloride.